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A solution that holds water

Researchers uncover why some drugs fail to suppress common protein
Stephanie Dutchen
By Stephanie Dutchen
Oct. 23, 2022

Name a biological function, and proteins called integrins are probably involved in it. Together, the 24 members of the integrin family allow cells to attach to one another and to the matrix that surrounds them. They help cells decide what to become, where to go, how to respond to their environments, and when to grow, divide or die.

Integrins’ ubiquity and versatility also mean that when cells bearing them go awry, these proteins can contribute to a range of diseases, from autoimmune diseases to cancer.

Integrins connect cells’ fibrous cytoskeletons, shown here, with the matrix that surrounds them.
Xiaowei Zhuang/HHMI/Harvard University/Nature Publishing Group
Integrins connect cells’ fibrous cytoskeletons, shown here, with the matrix that surrounds them.

The FDA has so far approved six drugs that reduce the activity of specific integrins to treat illnesses such as multiple sclerosis and ulcerative colitis and to prevent blood clots from forming. To the disappointment of scientists, doctors and patients, however, other promising candidates have failed in clinical trials and curtailed integrins’ potential as treatment targets.

New work led by researchers at Harvard Medical School and Boston Children’s Hospital uncovers a reason for the failures — and offers a potential solution.

Taking a close look at an integrin involved in blood clotting, Timothy Springer at HMS and Boston Children's and colleagues found that failed drugs for two different integrins inadvertently encourage the integrins to open up into their “on” position, potentially driving integrin activity instead of quelling it.

The team revealed that in its closed or “off” position, the integrin contains a water molecule held in place by a series of chemical bonds. The integrin ejects the water molecule when activated.

The team made some of its discoveries using X-ray crystallography, a painstaking method for determining the molecular structures of proteins. These are some of the resulting diagrams of drugs bound to the clot-related integrin.
Fu-Yang Lin, Jing Li, Yonghua Xie, et al., Cell
The team made some of its discoveries using X-ray crystallography, a painstaking method for determining the molecular structures of proteins. These are some of the resulting diagrams of drugs bound to the clot-related integrin.

Once they learned what was happening, the researchers were able to design integrin blockers that coaxed the clotting protein into its “off” position by holding the water molecule in place with a nitrogen atom.

Further tests hinted that water molecules play the same role in other integrins, indicating that the team’s strategy could work more broadly.

The findings, published in the journal Cell on Sept. 15, forge a clearer path for drug development and deepen researchers’ understanding of how integrins work normally.

“The same water-harnessing design principle has already been extended to another integrin, and structural information suggests that researchers can design drugs to target further members of the integrin family to treat diseases that cause great suffering,” said Springer.

“It’s always gratifying to work on a project that is both scientifically and medically important,” he added.

This article was republished with permission from Harvard Medical School. Read the original.

 

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Stephanie Dutchen
Stephanie Dutchen

Stephanie Dutchen is manager of feature content and multimedia at Harvard Medical School.

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